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Posted: 7 September 2022 | Hannah Balfour (European Pharmaceutical Review) | No comments yet hydroxypropyl cellulose
Next generation capsule shells are not only vegan but have a lower moisture content, offering greater performance consistency and maximising product shelf life, says formulation expert.
The second most commonly used pharmaceutical dosage form, capsules, are anticipated to be a $5.2 billion market by 2030, growing from a 2020 value of around $2.4 billion.1 Here experts Torkel Gren of Recipharm and Dr Jnanadeva Bhat of ACG-Worldwide share key developments in capsules by answering four key questions.
Torkel Gren, Senior Director, Technology Officer & Strategic Investments, Recipharm: Several major trends have emerged in recent years in the capsule space. Firstly, we are seeing growing demand for new materials to replace the traditional gelatine capsule shell.
Dr Jnanadeva Bhat, Vice President – Formulation R&D (Pharma & Nutra), ACG-Worldwide: Although gelatine capsules remain the most popular capsules, advancements in materials sciences and chemistry have provided pharmaceutical formulation developers with a new vegan hydroxypropyl methylcellulose (HPMC) capsule for encapsulation. These have become more popular in the pharma industry in recent years.
Due to their compatibility, many of the new molecules launched as hard capsules over the last three years have been formulated in HPMC capsules”
Gren: One of the reasons for this is the growing importance of offering an alternative vegan capsule for patients who do not want to consume animal products. Gelatine also poses potential long-term performance challenges that can impact the shelf life of a product; for instance, it can become insoluble when stored in certain conditions, resulting in a capsule that will not release the drug. The next generation of shell materials replacing gelatine, such as HPMC, are not only vegan but have a lower moisture content, offering greater performance consistency and maximising product shelf life.
Dr Bhat: HPMC capsules not only offer the required dissolution performance but are compatible with various drug molecules and formulations – including hygroscopic and moisture-sensitive formulations. Hygroscopic formulations are those that readily absorb moisture, and they can cause brittleness in gelatine capsules. Due to their compatibility, many of the new molecules launched as hard capsules over the last three years have been formulated in HPMC capsules.
Gren: Another trend we are seeing is the development of more sophisticated capsules to serve as research tools in pharmaceutical development. For example, capsules have been created that allow for monitoring of external conditions, such as pH, and external control over drug release. These newly developed tools can be used in clinical research, for instance drug absorption studies, and can contribute to faster and more efficient development of oral pharmaceutical products.
Gren: Capsules offer a great solution to the challenge of how to create sophisticated modified-release products. By mixing different coated pellets or minitablets, numerous intricate and precise drug release patterns can be achieved.
Compared with other oral solid dosage forms (OSDs), capsules also offer the easiest method to achieve fixed-dose combinations (FDCs) of incompatible drug substances. By mixing coated granules, pellets or minitablets within a capsule, incompatible drug substances can be incorporated into a single dose without stability issues. This has benefits for those patients who are prescribed complex treatments requiring the administration of multiple active pharmaceutical ingredients (APIs), as it can reduce the number of daily doses to a single multi-APIs capsule, enhancing convenience and patient adherence in turn.
Dr Bhat: Chronic diseases where FDCs are employed include hypertension, diabetes, Human Immunodeficiency Virus (HIV) and tuberculosis (TB). FDCs also reduce the risk of developing drug resistance and support a synergistic effect.
The capsule is a versatile dosage form that can accommodate complex formulations; for instance, formulations that are difficult to compress can be easily encapsulated. The encapsulation process is simple, involving the filling of a capsule with a low dose of the API and minimum excipients. No complex equipment is required, as hard capsules can be filled using a small-scale manual or semi-automated filling machine during the development phase.
Advancements in capsule technology encapsulation machines also make it easier to develop the product and deliver it in reduced timescales.
Gren: When rapidly developing a product for clinical trials, capsules avoid the issue of ensuring sufficient compactability for a coherent tablet to form and make it more straightforward to vary the dose. Additionally, a placebo is simple to create by filling identical capsules with an excipient, such as lactose, starch or cellulose.
Gren: The main limitation of capsules is their size, as higher doses of drugs require capsules that are relatively large. Fortunately, capsules are generally smooth with an elongated shape, so even larger capsule sizes are relatively easy to swallow compared with some traditional OSDs. However, certain patients perceive the larger capsules required for some multi-API drug products, or those with complex controlled release profiles, as difficult to swallow. This can create challenges in terms of patient compliance. To combat this, work is being done to advance formulation development in order to further reduce the size of capsules for complex drug products to help optimise patient comfort.
Another drawback is that, traditionally, capsules have been slightly more expensive to produce than tablets, which is due to the cost of the capsule shell and a slightly slower manufacturing process over tablets. However, capsule filling is gradually becoming more efficient and several steps in tablet manufacturing, such as granulation and coating, can be quite time-consuming. As a result, in a growing number of cases, capsules are becoming a more cost-efficient solution than tablets.
Dr Bhat: As with any dosage form there are benefits and drawbacks. For instance, there is currently no enteric capsule available in the market that can be directly targeted for intestinal drug release. Enteric capsules are the preferred choice for intestinal drug and functional excipient delivery. They are currently under development and will open huge avenues for the pharmaceutical industry.
Gren: A further issue is that capsules tend to be more sensitive to high temperature and higher moisture compared with tablets. However, this problem is being addressed with the advent of new capsule materials that are less susceptible to such challenges, helping to maximise shelf life.
Gren: We will see a continued process of shifting from gelatine to HPMC and other new capsule materials. This is due to the increasing adoption of vegetarian diets, as well as greater uptake in markets with hot and humid climates. As the shelf-life limits of capsules are being overcome with these new shell materials, we will see even broader use of capsules among all oral drugs. New types of drugs, such as oral vaccines, will also be formulated as capsules.
There may also be growth in capsules for inhalation. We expect a steep increase in asthma and chronic obstructive pulmonary disease in low- and middle-income countries, which will lead to demand for cost-efficient inhalation medicine and inhalers. Dry powder inhalers using drug substance in capsules are relatively cost-efficient devices and the capsule filling is a simple process. We believe this represents an affordable solution for inhalation therapy.
Dr Bhat: Dry powder-inhalation drug delivery via hard capsules is being explored in new therapeutic segments including Parkinson’s disease, migraine and cystic fibrosis. Various research universities are also working on biomolecule and vaccine delivery via inhalation capsules for the treatment of diseases such as cancers and tuberculosis, where the drug dose is reduced and efficacy is improved.
Gren: Despite facing challenges such as the trend towards injectable medicine, as more and more new drugs are biologics requiring injection, and the emergence of alternative means of drug manufacturing, such as three-dimensional (3D) printing, the patient convenience of capsules – combined with their unique controlled-release benefits – convinces me that there will be a strong need for capsules in the coming decades.
Torkel Gren is Senior Director, Technology Officer & Strategic Investments at Recipharm.
Dr Jnanadeva Bhat is Vice President – Formulation R&D (Pharma & Nutra) at ACG-Worldwide.
Hannah Balfour is the Science Writer for European Pharmaceutical Review.
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